1. Field of the Invention
The present invention relates generally to the field of pharmacologically active preparations and particularly to pharmacologically active preparations that are useful in the treatment and/or prevention of infectious diseases (especially parasitic diseases such as malaria), as optimized naphthoquinones, acridones, quinolones, pyridones, anthraquinones, xanthones, and derivatives thereof having anti-parasitic activity is disclosed.
2. Related Art
Malaria has plagued mankind since the beginning of civilization and is believed to be responsible for roughly half of all human deaths that have ever occurred. Malaria remains the most significant parasitic disease in the tropics and sub-tropics, where it causes at least 300 million clinical episodes and claims 1.5 million victims each year.
With a worldwide resurgence in the incidence of malaria, the spread of multi-drug-resistant strains of Plasmodium falciparum, the emergence of chloroquine-resistant P. vivax, and the increasing resistance of Anopheline mosquitoes to insecticides, malaria remains an enormous threat to the millions of people who travel to the tropics and subtropics each year3.
Malaria is a worsening global health problem. The incidence of malaria continues to increase worldwide, due in part to the emergence of drug resistance. Initially observed in the late 1950's and early 1960's in South America and Southeast Asia, chloroquine-resistant Plasmodium parasites that are associated with the most virulent form of malaria, cerebral malaria, have now spread to all malarious regions of the world. Varney et al. (1994)55 (1997)56 and others report a strong correlation between cerebral malaria and neuropsychiatric symptoms, such as poor dichotic listening, ‘personality change’, depression, and, in some cases, partial seizure-like symptoms. The tropical neuralnesia resulting from the legendary malarial fevers is well known in endemic areas and has been documented throughout history.
Due to the spread of multi-drug resistance, mefloquine is currently the drug of choice in treating malaria. However, this drug is known to cause sleep disturbances, increased dream activity, and cause depression in some individuals.5 Ototoxicity and central nervous system effects are known to occur with mefloquine therapy and may be as common as 1 in 200 to 1,000 individuals.14,30,48,58 Resistance to mefloquine is now common and occurs in regions in which the drug is not in general use.
Replacement drugs are urgently needed to treat malaria. The endoperoxides, like artemisinin (derived from a Chinese herbal remedy extracted from the wormwood plant) are being used in other parts of the world for malaria therapy. However, the use of this remedy is limited by reports of ototoxicity and neurotoxic effects of the endoperoxides.6,7,49 More recently, severe reproductive toxicity in female rats has been reported in animals treated with artesunate and its active metabolite, dihydroartemisinin. These findings are mirrored in reports by others in several different animal models.9 
Another pharmaceutical used in the treatment of malaria is atovaquone. Atovaquone is combined with the agent proguanil in a formulation known as Malarone® for treatment of malaria. Used alone, resistance to atovaquone occurs rapidly and is linked to specific mutations in the parasite gene encoding cytochrome b, a major transmembrane subunit of the cytochrome bc1 complex central to the redox and proton pumping reactions occurring in the parasite mitochondrion.26,53 Mutations at or near the ubiquinol binding region of the protein seem to sterically hinder binding of atovaquone, with its rigid and bulky side chain.23,33 In order for the parasite to survive, such mutations must permit discrimination between the drug and ubiquinol binding to cyt b.
Floxacrine is a drug that was described by Raether of Hoechst in the 1970's and 80's.38,39,59 This acridinedione is active to some extent in vitro and in vivo against multi-drug resistant Plasmodium parasites but development of the drug was abandoned due to unacceptable toxicity. Winkelmann and Raether found that the fully aromatic acridone analog of floxacrine was only slightly active against Plasmodium parasites 59 (see their compound #111). The mode of action of floxacrine has not been determined. Suswam et al. have reported a modest cross-resistance between floxacrine and atovaquone in P. falciparum isolates and clones.47 
In spite of all this, the pursuit of products specifically aimed at tropical diseases is not considered to be sufficiently profitable to feature among the research priorities of most pharmaceutical companies.50,51 The panacea for malaria therapy would be the development of a long-lasting vaccine, but the recent failure of the SPf66 vaccine1,4 and unrealized potential of newer multi-component DNA vaccines,12 combine to indicate that a vaccine is a long way from reality.
A need continues to exist in the medical field for the development of safe, inexpensive anti-parasitic agents, especially agents that would be useful against multi-drug-resistant organisms such as P. falciparum and P. vivax. 